Herpesvirus saimiri (HVS) is a lymphotropic or gamma herpesvirus and causes malignant T-cell lymphomas in monkeys and rabbits. HVS is related to Epstein-Barr virus (EBV) as revealed by DNA sequencing. EBV plays an important role in fatal B-cell lymphomas of immunosuppressed patients, in Burkitt's lymphomas and nasopharyngeal carcinomas. HVS has been studied extensively and has become a unique animal model for viral oncogenesis. Further understanding of the molecular mechanisms by which HVS causes cancer, which is the long term goal of this grant, should help us to reveal how human lymphomas develop. The experimental approach of the planned studies is based on several novel findings; (i) A strain of HVS is highly oncogenic in rabbits. This strain can also infect and specifically expand human CD8 cytotoxic T cells (termed Herpesvirus Activated Killer or HAK cells) in vitro. (ii) These transformed cells express a viral collagen-like oncoprotein (orf 1) and four small U-like RNAs (HSURs). A viral protein (orf2) with homology to interleukin-11 (IL-11) may be expressed in tumor cells as supported by indirect evidence. (iii) Orf1 and orf2 are required for oncogenicity and for lL-2 independent growth in vitro and the two HSURs are also required for oncogenicity in rabbits. (iv) HSURs complex with a novel inducible 7Okd AUUUA-specific mRNA binding protein (AUBF7O) which is probably involved in stabilization of lymphokine and oncogene mRNAs. (v) HVS-transformed lymphocytes secrete lL-4 and express large numbers.of high affinity lL-2 receptors. These data support the hypothesis that orf1, orf2, and HSURs cooperate and contribute to malignant transformation of T cells and interact to activate lymphokines and/or their receptors. To unambiguously prove this hypothesis, more basic information is needed about the molecular mechanisms by which the viral gene products stimulate/transform T cells; these basic experiments are proposed in specific Aims 1-3. Aim 4 is designed to study interaction of various viral genes involved in T cell transformation. AIM1; Further characterize the collagen-like orf1 oncoprotein and identify host proteins interacting with orf1. AIM 2; Identify and characterize the IL-11-like putative protein (orf2) in transformed T cells and study its putative receptor. AIM 3: Identify, clone, and characterize the AUBF7O protein, study its binding with HSUR in transformed cells, and define its role in stabilization of mRNAs. AIM 4: Determine which viral gene(s) are involved in lymphokine activation and immortalization. Human T cells will be transfected with various HVS genes. Expression of lymphokines will be studied in both T cell lines and normal human T cells. If transformation is achieved, rabbit T cells will be re-inoculated into autologous rabbits.